Many people think the Food and Drug Administration’s (FDA) role is limited to licensing new drugs and medical devices, but it actually has a post-marketing role as well. Doctors and hospitals all round the US are required to report any and all adverse side effects to drugs. It’s not uncommon to find that drugs can pass through clinical trials involving only thousands of participants, but show side effects when millions start taking them. Obviously, many problems come from those who abuse the drugs in one way or another but, every now and again, serious problems emerge over time. Once a pattern emerges, the FDA can either change the labels on the drugs to give stronger warning to patients or, in the worst cases, withdraw the licenses for the drug to be used. Since withdrawal can have a dramatic effect on the manufacturer, the FDA prefers to improve the level of warnings unless the problems are too severe to ignore.

Doctors have been aware of the problems of serotonin syndrome (sometimes also called serotonin toxicity) for some years. It’s a potentially serious adverse side effect when people ingest too much serotonin. Perhaps it’s better to think of this as a form of poisoning caused when people take excessive dosages of one drug or mix different drugs together. The effects fall into four main classes:

• a change to metal status – you may become agitated, hallucinate or, in extreme cases, fall into a coma;
• the body may start to function erratically and your blood pressure rises, your heart races and your body suddenly loses or retains heat;
• loss of physical co-ordination; and/or
• nausea, vomiting and diarrhea.

In some cases, the result has been death, e.g. the high-profile case of Libby Zion in 1984 which produced a change in the law of New York limiting the working hours for medical postgraduates and requiring their close supervision by senior physicians at all times. Thus, the FDA is not reacting to a new problem, but merely increasing the visibility of the warning notices as it affects all drugs containing serotonin.

In this instance, the warnings affect tramadol in the following ways. It always has been the case that an overdose of any of the opioid painkillers can cause this syndrome. Fortunately, this particular problem is relatively uncommon. Even those in the most severe pain understand the risks of exceeding the safe dosages are too dangerous to justify. Accidental overdose is almost unknown. So the most common problem arises with interactions between tramadol and other drugs with a serotonin content. The most dangerous combinations come with the classes of antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and triptans. The syndrome can arise even though you take the safe prescribed dose of the painkiller. So the warning is not so much about the painkillers themselves, but to alert people not to self-medicate. Since the rise of the online pharmacy industry, too many people have been buying drugs without a prescription – that means without talking through the risks with a doctor. Obviously, a doctor with access to a person’s medical history would immediately identify the dangers and either change the dosages or change the drugs. When people rely on recommendations from friends or the information they glean from the internet to decide what drugs to take, they can be putting themselves at risk. Hopefully, this new warning will prevent problems and keep people safe.

Once formed, habits are difficult to break. It always just seems easier to go on as you have before. This can become a serious problem when science gets in the way of the habits. If you look at the world of adverts in print and the media, you will see opioids recommended as the sure-fire drugs to use as painkillers, no matter what the pain. It carries on in the venerable tradition of the slogan, “Beecham’s Pills cure all ills”. The idea of a panacea – one pill to rule them all, as The Dark Lord of Mordor might have said – has been around since the beginning of time. This is fair game for the marketers to use when talking to the public, but the same thinking has entered the training manuals for the medical profession. Sit in lectures for student doctors and you will hear the same story that opioids are the first line of defense when it comes to moderate to severe pain. Once you have the source of the prescriptions in on the group think, the habit is almost impossible to break.

The monitoring and review process put in place after a drug is released into the market is designed to catch any unexpected side effects. If evidence of problems emerges, the FDA can require the manufacturer to change the warnings on the label or, in the worst cases, withdraw the drug from the market. But this monitoring process is not designed to catch the drugs that are ineffective. If no-one has an adverse reaction when taking it, no report is filed with the FDA. It’s safe so who cares whether it works. All this brings us to the Cochrane Collaboration. This is a non-profit group where researchers sift through and analyze existing published medical research to see whether there are any consistent patterns – what might not be apparent in one clinical trial involving two hundred participants might be identified when you compile the results from fifteen different trials, each involving two hundred participants. Two recently published Cochrane Reports have concluded that opioids should not be routinely prescribed to patients even with severe pain from hip and knee osteoarthritis.

In both Reports, the independent conclusions were that the adverse side effects outweighed the benefits and that tramadol, as the leading opioid, was no more effective than the strongest NSAIDs. The first Report consolidated the results from ten trials involving a total of just over 2,250 participants and concluded that there was little pain relief and minimal improvement in mobility. With higher dosages, one in twelve participants experienced adverse side effects. The second Report consolidated the results from eleven trials involving 1,020 participants and found little difference between the effectiveness of tramadol and the placebo. This leads to a somewhat controversial conclusion. That doctors should not routinely prescribe opioids for the treatment of hip and knee osteoarthritis. There should be a careful discussion of treatment options including weight loss, physical therapy and exercise, and a detailed explanation of all the adverse side effects to be expected. This new research does not change the general acceptance of tramadol as an effective painkiller. All it does is confirm that there is no such thing as one pill to cure all ills.